The goal of this program is to elucidate age-related changes in neurons which are likely to be involved in the reduced functional capacity and pathology of the nervous system in aged humans. The program consists of three projects: Aging changes in the Dynamics of the Neuronal Cytoskeleton Human Neurofilaments in Aging Mechanism of Aging at the Neuromuscular Junction We combined the approaches of morphology, electrophysiology, biochemistry and neuropathology to study the changes in the capacity of aging neurons to maintain and regenerate the axon and its synaptic connections. Dr. Lasek's project deals with the changes in the dynamic properties of the cytoskeleton, particularly neurofilaments, during the normal course of maturation and aging in laboratory mammals. His premise is that changes in the cytoskeleton play an important part in the functional changes of aged neurons. Dr. Gambetti will be studying the composition and properties of pathological neurofilaments from aged human brains. His primary objective is to identify the proteins which comprise the neurofibrillary tangles that occur in the brains of patients with Alzheimer's presenile dementia. Dr. Robbins' goal is to elucidate age changes at a well-understood prototypic chemical synapse--the neuromuscular junction. He will further analyze unique age changes in transmitter release and the underlying alterations in elemental presynaptic membrane properties. These studies on the mouse will be extended to human neuromuscular junctions. Thus, our program brings three laboratories together which are investigating related aspects of neuronal structure and function. The combined goal of this effort is to identify the cellular and biochemical mechanisms which give rise to age-changes in neurons and which predispose the nervous system to age-related pathology.